Tangeretin alters neuronal apoptosis and ameliorates the severity of seizures in experimental epilepsy-induced rats by modulating apoptotic protein expressions, regulating matrix metalloproteinases, and activating the PI3K/Akt cell survival pathway
Tangeretin alters neuronal apoptosis and ameliorates the severity of seizures in experimental epilepsy-induced rats by modulating apoptotic protein expressions, regulating matrix metalloproteinases, and activating the PI3K/Akt cell survival pathway
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DOI：
10.1016/j.advms.2016.11.011
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发表时间：
2017-09-01
影响因子：
2.7
通讯作者：
Liu, Xue-wu
中科院分区：
文献类型：
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作者：
Guo, Xiao-qian;Cao, Yu-ling;Liu, Xue-wu
目的：癫痫是一种复杂的神经紊乱，以反复发作为特征。尽管最近在癫痫药物治疗方面取得了进展，但由于药物的相反作用，其治疗仍然是一个挑战。因此，寻找具有神经保护作用且副作用小的新型抗癫痫药物具有重要的研究价值。因此，本研究利用匹罗卡品诱发癫痫大鼠模型评估橘皮苷的治疗效果。材料与方法：雄性Wistar大鼠分别以50、100、200 mg/kg剂量口服橙皮苷10 d，第10天腹腔注射匹罗卡品（30 mg/kg）。随后，使用尼氏染色和末端脱氧核苷酸转移酶（TdT）介导的dUTP缺口末端标记（TUNEL）测定程序评估神经元变性和凋亡。此外，采用Western blot方法检测磷脂酰肌醇-3激酶（PI3K/Akt）通路蛋白、cleaved caspase-3、Bad、Bcl-2、Bcl-xL和Bax的表达。结果：橘皮苷降低大鼠癫痫发作评分和首次发作潜伏期，有效激活匹罗卡品诱导的PI3K/Akt信号抑制。此外，橘皮素还能有效调节线粒体中凋亡诱导因子（AIF）水平和凋亡通路蛋白的表达。癫痫引起的基质金属蛋白酶(MMPs)-2和-9的活性和表达升高也受到调节。结论：橘皮素通过激活PI3K/Akt信号通路和调控MMPs，对匹罗卡平诱导的癫痫发作具有明显的神经保护作用。(C) 2017比亚韦斯托克医科大学。Elsevier B.V.版权所有。
Purpose: Epilepsy is complex neural disarray categorized by recurring seizures. Despite recent advances in pharmacotherapies for epilepsy, its treatment remains a challenge due to the contrary effects of the drugs. As a result, the identification of novel anti-epileptic drugs (AEDs) with neuroprotective properties and few side effects is of great value. Thus, the present study assessed the treatment effects of tangeretin using a rat model of pilocarpine-induced epilepsy.Materials and Methods: Separate groups of male Wistar rats received oral administrations of tangeretin at 50, 100, or 200 mg/kg for 10 days and then, on the 10th day, they received an intraperitoneal injection of pilocarpine (30 mg/kg). Subsequently, neuronal degeneration and apoptosis were assessed using Nissl staining and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay procedures. Additionally, the expressions of phosphatidylinositol-3-kinase (PI3K/Akt) pathway proteins, cleaved caspase-3, Bad, Bcl-2, Bcl-xL, and Bax were determined using Western blot analyses.Results: Tangeretin reduced the seizure scores and latency to first seizure of the rats and effectively activated the pilocarpine-induced suppression of PI3K/Akt signaling. Additionally, tangeretin effectively regulated the levels of apoptosis-inducing factor (AIF) in mitochondria as well as the expressions of apoptotic pathway proteins. Seizure-induced elevations in the activities and expressions of matrix metalloproteinases (MMPs)-2 and -9 were also modulated.Conclusion: The present results indicate that tangeretin exerted potent neuroprotective effects against pilocarpine-induced seizures via the activation of PI3K/Akt signaling and the regulation of MMPs. (C) 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.